Stimulation of alpha/1-adrenergic receptors increases the action potential duration and the force of contraction in cardiac myocytes via several modifications of cellular function. One important mechanism is the inhibition of potassium channels. Although the electrophysiological description of alpha-1-adrenergic inhibition of potassium channels was reported over a decade ago, further progress in understanding this system has lagged in comparison to our understanding of other neuromodulatory systems. In large part this limited progress has been due to the lack of suitable model systems in which a range of technical approaches can be combined to direct address this problem. We propose to study alpha/1-adrenergic modulation of two potassium channels that are expressed in cardiac myocytes: the inward rectifier channel (I/k1) and the transient outward channel (I/to). We will use two cell systems in which to analyze the mechanisms of inhibition: a heterologous expression system and a transfected cultured myocytes system. Most importantly, hypotheses concerning the nature of alpha/1-adrenergic modulation of potassium channels expressed in these cells will be studied using a combination of molecular, electrophysiological and protein chemistry approaches. It is currently uncertain how the alpha/1-adrenergic pathway modulates key effector molecules such as potassium channels in cardiac myocytes. This pathway in important in determining alpha-adrenergic effects on repolarization (affect heterogeneity of action potential duration and susceptibility to arrhythmias) and impulse initiation (important concerning arrhythmogenesis). Determination of the molecular mechanisms involved is essential to developing an understanding for how the sympathetic nervous system and its neurotransmitters can act to trigger cardiac arrhythmias.